1-(3-aminopyrazinoyl)semicarbazides,1-(3-aminopyrazinoyl) - thiosemicarbazides,and method for their preparation

ABSTRACT

1-(3-AMINOPYRAZINOYL)SEMICARBAZIDES AND -THIOSEMICARBAZIDES ARE DESCRIBED THAT CAN OPTIONALLY BE SUBSTITUTED IN THE 5- AND/OR 6-POSITION OF THE PYRAZINOYL MOIETY AND ADDITIONALLY OPTIONALLY SUBSTITUTED ON THE CARBAZIDE NITROGEN ARE PREPARED BY THE REACTION OF THE SELECTED 3-AMINOPYRAZINOIC ACID HYDRAZIDE AND THE SELECTED ISOCYANATE OR ISOTHIOCYANATE. THE PRODUCTS POSSESS NATRIURETIC AND DIURETIC PROPERTIES WITHOUT KALURETIC PROPERTIES AND ARE USEFUL IN THE TREATMENT OF CONDITIONS ASSOCIATED WITH AN ABNORMAL RETENTION OF SODIUM AND CHLORIDE IONS SUCH AS THE TREATMENT AND MANAGEMENT OF EDEMATOUS CONDITIONS.

"United States Patent 1-(3-AMINOPYRAZINOYL)SEMICARBAZIDES, 1-(3- AMINOPYRAZINOYL) THIOSEMICARBAZIDES,

AND METHOD FOR THEIR PREPARATION Edward J. Cragoe, Jr., and John B. Bicking, Lansdale,

and Kenneth L. Shepard, Ambler, Pa., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Nov. 13, 1968, Ser. No. 775,543

Int. Cl. C07d 51/76 U.S. Cl. 260-250 13 Claims ABSTRACT OF THE DISCLOSURE This invention is concerned with novel 1-(3-aminopyrazinoyl)-semicarbazides and -thiosemicarbazides that possess useful saluretic and diuretic properties as well as novel processes for their preparation. The products of this invention are useful therefore in the treatment or management of edema and other abnormalities resulting from the retention of excess quantities of sodium and fluid by the animal organism.

The 1-(3-aminopyrazinoyl)-semicarbazides and -thiosemicarbazides of this invention have the structural formula N X NH;

H 1 Y \N CON NH 0 NHR wherein:

X is selected from hydrogen and amino of the structure NR R wherein NR R represents an unsubstituted or a substituted amino group wherein R is selected from (1) hydrogen,

(2)alkyl, preferably lower alkyl or from 1 to about 6 carbon atoms either straight or branched chain and either saturated od unsaturated, e.g., methyl, ethyl, propyl, isopropyl, allyl, propenyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl hexyl and the like,

R is selected from (1) hydrogen,

(2) alkenyl, preferably lower alkenyl of from 3 to about 5 carbon atoms, e.g., allyl, propenyl or the like,

(3) alkynyl, preferably lower alkynyl of from 3 to 5 carbon atoms, e.g., propargyl and the like,

(4) lower cycloalkyl of from 3 to about 7 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like,

(5) mononuclear aryl, especially phenyl, either unsubstituted or substituted, such as with halo, e.g., chloro, bromo, or fluoro, lower alkyl of 3,555,024 Patented Jan. 12, 1971 from 1 to about 3 carbon atoms, e.g., methyl, ethyl, and propyl, or lower alkoxy, e.g., methoxy, ethoxy, propoxy, and the like.

(6) lower alkoxy, preferably lower alkoxy of from 1 to 4 carbon atoms, e.g., methoxy, ethoxy, isopropoxy and the like,

(7) substituted amino selected from pyridylamino and pentamethyleneamino,

(8) alkyl, preferably lower alkyl of from 1 to about 6 carbon atoms either straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl and the like, either substituted or unsubstituted with one or more substituents selected from (a) lower alkoxy of from 1 to about 3 carbon atoms, e.g., methoxy, ethoxy, propoxy and the like,

(b) lower cycloalkyl of from 3 to about 6 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl and the like,

(0) heterocyclic group of 5 or 6 nuclear members and containing one or more hetero atoms selected from oxygen and nitrogen, especially furyl and pyridyl,

(d) mononuclear aryl, especial phenyl, either unsubstituted or substituted with such as halo, e.g., chloro, bromo, or fluoro, lower alkyl of from 1 to about 3 carbon atoms, e.g., methyl, ethyl, or propyl, or lower alkoxy of from 1 to about 3 carbon atoms, if, methoxy, ethoxy, propoxy and the (e) -NR R wherein R is selected from (1) alkyl, preferably lower alkyl of from 1 to about 5 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl and the like,

(2) lower alkylcarbonyl, of from 2 to about 3 carbons, e.g., acetyl, propionyl, and the like,

R is alkyl, preferably lower alkyl of from 1 to about 5 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl, and the like,

R and R when lower alkyl can be linked together either directly or through a hetero atom such as nitrogen or oxygen to form a heterocyclic ring with the nitrogen to which they are attached, e.g., piperidino, pyrrolidinyl, morpholino, piperazinyl, N-lower alkyl piperazinyl, and the like;

R and R when lower alkyl can be linked together either directly or through a hetero atom such as nitrogen or oxygen to form a heterocyclic ring with the nitrogen atom to which they are attached forming, e.g., piperidino, pyrrolidinyl, morpholino, piperazinyl, N-lower alkyl-piperazinyl, and the like;

Y is hydrogen, halogen, preferably chloro, bromo or iodo,

phenyl, lower alkyl;

Z is selected from oxygen and sulfur; and

R is selected from hydrogen, lower alkyl, lower alkenyl,

phenyl, halo(chloro or bromo)-phenyl, and phenyllower alkyl (C In the foregoing definitions unless otherwise noted, the lower alkyl radicals advantageously have from 1 to 5 carbon atoms and are either straight or branched chain, the lower alkenyl radicals have from 3 to 5 carbon atoms and the cycloalkyl radicals have from 3 to 6 nuclear carbons and are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The products of this invention are prepared by the 3 4 reaction of a 3-an1inopyrazinoic acid hydrazide with the In the following text illustrative methods for making selected isocyanate or isothiocyanate according to the intermediates and their use in preparing the novel prodfollowing scheme: nets of this invention are detailed in the following order:

N N X N112 X NH: 7

Y i l Z=C=NR1 a i l '11 Ii Nil 1 1 COI\lINlIz COI\llI\ c R II III I This reaction preferably is carried out in the presence Of 10 (A) Preparation of the alkyl 3amino-5-X-6-Y-pyrazinoa solvent and with heating from about steam bath temates perature up to the reflux temperature of the reaction mix- (B) Preparation of the hydrazides from the pyrazinoture. The reactants can be employed in equimolecular ates of (A) quantity although an excess of one or the other can be (C) Examples illustrative of the preparation of the novel used, usually 311 CXCESS Of the cyanate, III. Solvents such pyrazinoylse nicarbazides from the hyd azides of (B) as l r alkanols, acetonitrile, acetic i dilute y (D) Examples illustrative of the preparation of the novel Chloric acid Py can be p y the macho pyrazinoylthiosemicarbazides of this invention from medium although other usual solvents can be used as h h d id f (13) well.

Although many of the pyrazmolc acid hydrazides, II, SECTION A are known compounds, those that are not known can be prepared by known methods including reaction of an 1k 1 pyrazinoate d h d i Preparation of alkyl 3-amlno-5-X-6-Y-pyrazinoates The intermediate esters generally are prepared by one of the processes shown below. Many esters, however, pre- A 1; h l 3.amino 5-dimethylamino-6-chloropyraviously have been described, some of which were made i A suspension f h l 3 i .s,6 di hl by methods other than those illustrated below which i oat (178 g., 0.8 mole) in 2-propanol (1.1 liters) methods w u also e useful in preparing the desired is stirred while dimethylamine 200 g., 4.44 moles) in 2- ester starting mat -ria spropanol (2 liters) is added, and then the mixture is refluxed for an hour. The product that separates is removed by filtration and dried. The yield is 177.2 g. (97%). After recrystallization from methanol the methyl 3-amino- 5 dimethylamino 6 chloropyrazinoate melts at 145.5-

146.5 C. AnaIysis.Calcd for C H ClN O (percent): C, R5 41.66; H, 4.81; N, 24.29. Found (percent): C, 41.73; H, N R5 4.52; N, 24.24. Cl 4 NH; \NvII Base R/ l1 1 Y Cooi\ik A-2: Preparation of methyl 3-amino-5-(2,2-pentamethyl- Y 000A R N enehydrazino)-6-chloropyrazinoate IV V A mixture of methyl 3amino-5,6-dichloropyrazinoate (22.2 g., 0.1 mole), N-aminopiperidine (10.0 g., 0.1 mole), triethylamine (15 ml.), and dimethyl'sulfoxide (100 ml.) is warmed on the steam bath With stirring for three hours. The solution is diluted with Water (350 ml.) and the solid that separates is collected and dried yielding N N 25.6 g. of methyl 3-amino-5-(2,Z-pentamethylenehydra- X il X NHQ 0 zino)-6-chloropyrazinoate, M.P. l95-202 C. Recrystalj j TE lization from acetonitrile or butyl chloride gives material Y coon Y COOAlk with M.P. 207-209 C.

N N Analysis.-Calcd for C H ClN O (percent): C, VI VII 46.24; H, 5.65; N, 24.51. Found (percent): C, 46.39; H,

A3: Preparation of methyl 3-amino-5-[2-(2-pyridyl)- hydrazino]-6-chloropyrazinoate.-A mixture of methyl 3- amino-S,6-dichloropyrazinoate (22.2 g., 0.10 mole), 2- hydrazinopyridine (11.0 g., 0.10 mole) triethylamine (22 0 ml.), and dimethyl sulfoxide (100 ml.) is heated on the The Products of this invention Can he administfifed steam bath for three and one-half hours. The reaction mixt m n or animals in the form of P tablets. capsules, ture is diluted with Water (250 ml.) and the solid that elixirs, injectable preparations and the like and can comforms is collected and dried, yielding 29.8 g. of methyl 3- prise one or more of the compounds of this invention as ino 5 [2-(2-pyridyl)hydrazino]-6-chloropyrazinoate, the only essential active ingredient of the p a m ce 35 M.P. 20l205 C. Recrystallization from acetonitrile gives formulation or the novel product(s) can be combined in i l i h M 203 20 C pharmaceutical formulations with other diuretic agents or A nalysis.calcd for C H ClN O (percent): C indeed other therapeutic agents. The products of this in- 4433; H 3%; N, 2 52 Found (percent); C 4488- vention advantageously are administered at a dosage range 3 79; N7 2332 f frOm about 5 g P y 10 about 750 PQ day By employing substantially the same method described or ata m g e v r dosage atthe physlcians in Al, above, but substituting for the dimethylamine, (hscffitloh, p 'f y subdwlded amfmhts on a 2 to 4 equimolar quantities of the amines identified in Table I times a y feglmeh- These formulatlohs can be p there is obtained the corresponding methyl 3-amino-5- ared by the usual methods for making unit dosage forms substituted-amino-6-chloropyrazinoate products identified of compounds for oral or parenteral administration. in Table I according to Equation A.

TA BLE I.EQUATTO N A N R N 01 R5 \NH \N i 11 Rfl/ i Cl N COOGEL'; Cl- N -COOCHa Analysis Calculated Found R R M.P., G. Product, Formula C H N C H N Preparation:

A-4 CHEC-CHz- H 168-169 C BHQC1N402 44. 92 3. 77 23. 28 44. 82 3. 73 23. 09

11-5--- CH3O CHzCHr- H 142-144 C9 l3N-1 3C1 41. 47 5. 03 21. 49 41. 56 5.03 21. 38

11 190-101 C 2H 2C1N502 40. 07 4. 12 23. 85 49. 39 4. 06 23. 88

H 170-171 C gHnNgOzCl 49. 07 4. 12 23. 85 40. 36 4. 18 23. 61

H 208-210 C H14N503 1 41. 75 4 90 42. 34 42. 04 4. 85 24. 69 H 175-179 01111150121503 H 180-182 CnHmNaOaOl 43. 78 5 44. 21 5. O7 H 114-116 C i2H2oN502C1 47. 76 6. 68 23. 21 47. 88 6. 63 23. 13 A-12 (O 2H5) 2N( C H2) 2 0 H3- 51-54 0131122 C1N5 O 2 49. 44 7. 02 22. 18 49. 65 6. 67 22. 30 (CH3)2N(CI'12)3' 1'1 108-109 CHH18N502C1 45. 91 6. 30 24. 34 46. 30 6. 26 24. 43 .4-14 (CH N(CH2)4- H 170-171 cI2 20C1NbO2 1 42. 61 6. 20 42. 5. 67

A-15 N(CHz) 2- H 121-122 C12H18N5O 2 C1 48. 08 6. 05 23. 37 48. 31 6. 40 23. 76

11-16 C HaN /N( C Hz) H 148-149 C nHzaNe 0 2 Cl 49. 05 6. 76 24. 52 48. 95 6. 64 24.

11-17 O N--( CH2) 3' 11 158-160 Cl3H1DN5O 301 47. 34 6. ll 21. 24 47. 41 6. 04 5. 17

14-18 CH (CH2) 2- CH3 83-85 C1uH15N4 C102 46. 42 5. 84 21. 66 46. 5. 21.70

A-19 -CH2CHzNCH2CH2 143-145 C12H1BN502C1 48. 08 6. O5 23. 36 47. 07 6. 11 23. 19 A-20 -CHCH2O-CH2CH2- 197-198 CroHmNqOaCl 44. 04 4. 20. 55 44. 32 4. 74 20. 67

11-21 N CH2) 2- H 157-158 G1 Hz5C1N5Ot (111316818) 47. 28 6. 07 16. 22 47. 43 6. 06 16. 55

1l-C Hn 11-22 (CH3) 2N( CH2) 3' CH3 202-203 CrzHzoClNsOz (H C1) 42. 61 6. 26 20. 71 42. 51 6. 09 21. 02

The following compounds also are prepared by the method described in A-l, above, by replacing the dimethylamine with an equimolecular quantity of (A-23 2- (N-acetyl-N-ethylamino) ethylamine (A-24) Z-piperidinoethylamine (A-25) 3-piperidinopropylamine thereby forming A-23 Methyl 3-amino-5- [2-(N-acetyl-N-ethylamino)ethy1- amino] -6-chloropyrazinoate A-24 Methyl 3-amino-S-(2-piperidinoethylamino)-6- chloropyrazinoate and A-25 Methyl 3-amino-5-(3-piperidinopropylamino) -6- chloropyrazinoate SECTION B Preparation of 3-amino-5-X-6-Y-pyrazinoic acid hydrazides acid hydrazide melting at 137l40 C. After crystallization from 2-propanol the compound melts at 142-145 C.

Analysis.Calcd for C H N ClO (percent): C, 41.79; H, 5.84; N, 32.49. Found (percent): C, 42.00; H, 6.05; N, 32.10.

B-2: Preparation of 3-amino-5-(2,2-pentamethylenehydrazine)-6-chloropyrazinoic acid hydrazide.A mixture of methyl 3-amino 5 (2,2 pentamethylene-hydrazino)-6-chloropyrazinoate (2.86 g., 0.01 mole), hydrazine 0.68 g.), dimethylformamide (5. ml.), and ethanol (30 ml.) is heated on the steam bath with stirring for 5 hours then cooled to room temperature. The white solid is collected, washed with a little ethanol, and dried to yield 1.97 g. of 3-amino-5-(2,2-pentamethylenehydra- Zin0)-6-chloropyrazinoic acid hydrazide, M.P. 218221 C. Recrystallization from ethanol gives material melting at 221-222 C.

Analysis.Calcd for C H ClN (percent): C, 42.03; H, 5.64; N, 34.22. Found (percent): C, 42.01; H, 5.71; N, 34.38.

B-3: Preparation of 3 amino 5 [2 (2-pyridyl) hydrazinol]-6-chloropyrazinoic acid hydrazide.A mixture of methyl 3-amino-5-[2 (2 pyridyl)-hydrazinol] 6-chloropyrazinoate (11.75 g., 0.04 mole), hydrazine (64% in water, 50 ml.), and ethanol ml.) is heated to reflux for four hours. The mixture is diluted with water TABLE II.Contin'ued End product Analysis Ester Calculated Found Preparafrom M.P., ration p'repn. X Y O. Formula H N C H N 11-29 11-17 0 N(CH2) NH Cl 183-4 O1zH2uOlN O2 43.70 6.11 29.73 44.24 6.17 20.00

13-30 NH 01 194-5 GUI-1110mm 47.40 3.98 30.16 47.39 4.02 30.32

13-31 A-l (CH3)2N- Cl 103-5 OyHnClNsO 36.45 4.81 36.44 36.51 5.01 36.84

C53 13-32 /N-- Q- 153-4 CmHmNoO 57.34 5 02 30.86 57.77 5.81 30.71

CH3 CH3 B-33 /N C1 134-0 CsHlaNaClO 30.27 5.36 34.35 30.36 5.51 34.39

CQHE CE: 13-34 A-18 /N C1 133-6 CnHxaClNaO 41.78 5.84 32. 40 41.02 5.84 32.31

13-35 A-21 N(CH2)2NH- C1 88 C12H22C1N O 45.63 7.02 31.05 45.72 6.73 31.43

n-C4He B-36 N- Cl 181-2 CQHBCINGO 42.11 5.10 32.74 42.45 5.06 32.86

13-37 CHa-N N- Cl 180-90 CmHC1N O 27.59 3.71 28.11 3.62

13-38 A-19 CzHaN N Cl 168-70 CuHmC1N1O 44.07 6. 05 44.20 5.66

B-39 A- O N-- 01 190-02 CaHmCINqO 39.64 4.80 30.82 39. 43 4.57 30.64

Ester Ester from from Prepn. X Y Prepn. X Y

Preparation:

B40 HzN- 13* 13-49 Q-omcnmnc1 0 B-41 HzN- I 13-50 m vnmm- 01 13-42 -NH- 01 B-51 A-23 C2H N(CH2)2NH 01 B-43 A-4 CH=C CHzNI-I- Cl B-52 A-24 (OH2)2NH C1 13-44 CH2NH C1 13-53 A- (CH2)3NI'I- 01 13-45 CHa(CH3O)N- 01 13-54 C1NH o1 OH B-46 CFaCH2NH- C 13-55 /N CH 13-47 CF3CH2CH2NH- C 13-56 N 01 CHz=CH-CH2 CH3 13-48 omQ-crmm- 01 13-57 N- 01 n-C4H9 1 Ester known unless otherwise noted.

11 SECTION C Preparation of l-(3-amino-5-X-6-Y-pyrazinoyl)semicarbazides NOTE.Th6 hydrazide intermediate is known unless otherwise noted.

EXAMPLE 1 1-(3-amino-6-chloropyrazinoyl -4-phenylsemicarbazide To a boiling mixture of 3-amin0-6-chloropyrazinoic acid hydrazide (3.76 g.; 0.02 mole) in acetonitrile (125 ml.) is added phenyl isocyanate (2.38 g.; 0.02 mole). The reaction mixture is heated at reflux for one hour and then allowed to stand at room temperature overnight. The solid product that precipitates is collected giving 6.0 g. (97%) of 1 (3-amino-6-chloropyrazinoyl)-4-phenylsemicarbazide, M.P. 220 C. After recrystallization from a mixture of acetic acid and ethyl alcohol the product melts at 215- 217 C.

AnaIysis.Calcd. for C R CIN O (percent): 46.99; H, 3.62. Found (percent): C, 47.06; H, 3.55.

EXAMPLE 2 1-(3-amino-6-chloropyrazinoyl)semicarbazide A mixture of 3-amino-6-chloropyrazinoic acid hydrazide (5.00 g.; 0.027 mole) and potassium cyanate (4.38 g., 0.054 mole) in 50 ml. of water and 5 ml. of concentrated hydrochloric acid is heated on the steam bath for two hours. The reaction mixture is cooled to room temperature in an ice bath. The solid that separates is collected and dried to give 5.20 g. (85%) of 1-(3-amino-6-chloropyrazinoyl)semicarbazide, M.P. 235-248" C. (dec). Recrystallization from absolute ethanol gives material melting at 249251 C. (dec.).

AnaIysis.Calcd. for C H ClN O (percent): C, 31.24; H, 3.06; N, 36.44. Found (percent): C, 31.55; H, 3.29; N, 36.50.

EXAMPLE 3 1-( 3,5 -diamino-6-chloropyrazinoyl) semicarbazide dimethylformamide solvate A mixture of 3,5-diamino-6-chloropyrazinoic acid hydrazide (5.00 g., 0.025 mole), from preparation B-4, and potassium cyanate (4.06 g., 0.050 mole) in ml. of water and 5 ml. of concentrated hydrochloric acid is heated on a steam bath for two hours. The reaction mixture is cooled in an ice bath and the solid that separates is collected and dried. Recrystallization from dimethylformamide gives 1-(3,5-diamino-6-chloropyrazinoyl)semicarbazide dimethylformamide solvate, in the form of a light orange colored solid, yielded 5.0 g. (92% M.P. 300 C.

Analysis.-Calcd. for C H ClN O (+C H NO) (percent): C, 33.91; H, 4.74; N, 35.16. Found (percent): C, 33.70; H, 4.55; N, 35.05.

EXAMPLE 4 1- 3,S-diamino-6-chloropyrazinoyl) -4-allylsemicarbazide A mixture of 3,5-diamino-6-chloropyrazinoic acid bydrazide (5.00 g., 0.025 mole), from preparation B-4, and allyl isocyanate in pyridine ml.) is heated on a steam bath for two hours. The resulting solution is diluted with water (250 ml.) and allowed to stand in an ice bath whereupon a yellow solid separates out of solution. This solid is collected by filtration and dried yielding 2.6 g. (46%) of 1 (3,S-diamino-6-chloropyrazinoyl)-4-allylsemicarbazide, M.P. grad. dec. over 200 C. Recrystallization from nitromethane yields material that gradually decomposes above 200 C.

AI1aIysis.Calcd. for C H C1N O (percent): C, 37.83; H, 4.24; N, 34.32. Found (percent): C, 37.97; H, 4.48; N, 34.58.

Additional 1-(3-aminopyrazinoyl)semicarbazide compounds prepared by the process described in Example 1 are identified in Table III. These products are prepare d by reacting equimolecular quantities of the 3-aminopyrazinoic acid hydrazide II, having the substituents X and Y identified in the table with the isocyanate IIIa, having the substituent R identified in the table to give the product I-a, having the substituent X, Y, and R given in Table III.

TABLE 111 N N X{ I NH OZCZNR, X I NH O Y ICONHNH- Y 'o0N11NHi :-NBR

\\\N i \N II III-a l-a Hydrazide from Prepn. X Y R1 Example No.:

5 H or oH2oH=cHz s B-l (02H5)2N- Cl CHCH=CH2 7 B2 N-NH o1 -c1 N s 13-3 NHNH- c1 -oH2--c,n

cmNH- o1 onicu=cu CgH NII 01 -cu; ll-C3H7NH Cl C3H -n CH2=CHCILNII c1 -CH2CII=CIIz 11-G4H9NH C1 C4Hg-n CHNH- 01 cm 15 13-11 (CHa)aCNH- c1 crncu=cm 16 13-12 NH- o1 cu2c1 =c112 17 H I cmcu=cm 1s 15-14 CH3OCH2CH2NII c1 -oi1zcu=cn2 19 13-15 C1CH:NII c1 -cmcn=c1r TABLE IlI.Conti1ruo(l Hydrazide from I Prcpn. X Y R1 Example No.1

(F113 46 15-20 (CglI )gN(Cll:)zN-- Cl CHzCl-I=CH CH 4? 13-55 )N- CI'I CH5 c0011. 48 13-13 CI'I;I I(CHg)gNII Cl CH 49 13-40 H N- Br -CI-IQCII=CII2 50 13-41 H N 1 CH:CH=CH2 51 13-42 i NIlo1 CH3 52 13-43 CH=CCH NII- 01 CH;

53 13-44 -CHgNI-I 01 CH;;

54 13-54 Cl- N1I- Cl -CH2C5H5 55 13-40 CFJCIIQNH Cl CI 5G 13-47 CF CIIgCII2NII Cl CILCH=CH2 57 13-48 c1r o1n1 111- c1 -o1no1r=01n 5s 13-45 -011:011.N11- o1 Amen-c611.

o 59 13-50 lCH- NI-I c1 Cl1uClI=Cllz 60 13-51 CgI-I N(CHQ) NII o1 CH5 61 13-52 N(CII2)QN1I Cl OsH:-n

02 13-53 N-(CII2)3NH o1 CaH7-n 1 Hydrazide known unless otherwise noted.

SECTION D Analysis.-Calcd. for C H CIN OS (percent): C, 27.53; H, 3.08; N, 37.47. Found (percent): C, 27.74; Preparation of 1-(3-amino-5-X-6-Y-pyrazinoyl)- 55 H, 2.88; N, 37.61.

thiosemicarbazides EXAMPLE 64 Note-The hydrazide intermediate is known unless I Otherwise noted l[3-am1no-5-(2-d1methylarn1noethylamino)-6-chloropyrazinoyl thiosemicarbazide EXAMPLE 63 0 3-amino-5-(2 dimethylaminoethylamino) 6 chloro- 1-(3,5-d1am1no-6-chloropyrazinoyl)thiosemicarbazide pyrazinoic acid hydrazide (10.92 g.; 0.04 mole), from Preparation B22, and potassium thiocyanate (7.76 g.; A {nlxtufe 0f 3,5-dlflmll'lo-6'Ch10Y0PY1'aZ1I101C acld 0.08 mole) are mixed with N hydrochloric acid ml.) hydrallde, from Preparanon mole) 3 and refluxed for 3 hours. The solution is cooled and and potassium thiocyanate (3.3 g.; 0.034 mole) in glacial acetic acid ml.) is heated on the steam bath for two hours. The reaction mixture is cooled to room temperature and the solid removed by filtration. The solid material is dissolved in hot dimethylformamide (20 ml.) and reprecipitated by addition of water to give 2.19 g. of 1-(3,5 diamino 6 chloropyrazinoyl)thiosemicarbazide, M.P. 241.5243 C. (dec.). After recrystallization from a mixture of dimethylformamide and Water, the material melts at 24Z,-244 C. (dec.).

17 Analysis.Calcd. for C H ClN OS (percent): C, 36.08; H, 5.08; N, 33.99. Found (percent): C, 36.43; H, 5.00; N, 33.23.

EXAMPLE 65 1- (3 ,5 -diamino-6 -chloropyrazinoyl) -4-allylthiosemicarbazide 3,5-diamino-6-chloropyrazinoic acid hydrazide (6.0 g.;

0.03 mole), from Preparation B-4, and allyl isothiocyanate (4.95 g.; 0.05 mole) are mixed with glacial acetic acid (120 ml.) and warmed on the steam bath for two 1-(3-am.ino-6-chloropyrazinoyl)-4-allylthiosemicarbazide A refluxing solution of 3-arnino-6-chloropyrazinoic acid hydrazide (21.41 g.; 0.15 mole) in Z-methoxyethanol (225 ml.) is treated with allyl isothiocyanate (17.85 g.; 0.18 mole) and refluxing is continued for two hours. The reaction mixture then is concentrated to a paste under reduced pressure and the residue is triturated with ethanol to give 26.28 g. (61%) of 1-(3-amino-6- chloropyrazinoyl) 4 allylthiosemicarbazide, M.P. 203- 205 C. Recrystallization from acetic acid gives the product in the form of orange prisms, M.P. 208209 C.

Analysis.Calcd. for C H ClN OS (percent): C, 37.70; H, 3.87; N, 29.31. Found (percent): C, 38.02; H, 3.80; N, 29.37.

EXAMPLE 67 1-(3-amino-6-chloropyrazinoyl)thiosemicarbazide A solution of 3-amino-6-chloropyrazinoic acid hydrazide (3.8 g.; 0.02 mole) and potassium thiocyanate (2.4 g.; 0.024 mole) in acetic acid (40 ml.) is heated one hour on the steam bath. The crystalline product that separates is collected on a filter and recrystallized from a mixture of isopropyl alcohol and water to give 1.7 g. (68%) of 1-(3 amino 6 chloropyrazinoyl)thiosemicarbazide, M.P. 236-237 C. (dec.).

Analysis.Calcd. for C H CIN -OS' (percent): C, 29.21; H, 2.86; N, 34.07. Found (percent): C, 29.55; H, 3.03; N, 34.30.

EXAMPLE 68 1- 3,S-diamino-6-chloropyrazinoyl) -4-phenylthiosemicarbazide A mixture of 3,5-diamino-6-chloropyrazinoic acid hydrazide (6.06 g.; 0.03 mole), from Preparation B-4, and phenyl isothiocyanate (6.0 ml.) in glacial acetic acid (120 ml.) is heated on the steam bath for one hour, cooled and diluted slowly with water (250 ml.) and set aside overnight. The solid that forms is collected and dried to give 6.4 g. (63%) of 1-(3,5-diamino-6-ch1oropyrazinoyl)-4-phenylthiosemicarbazide, M.P., depending upon the rate of heating, 206-208 C. (fast heating); 223-224 C. (slow heating), both with decomposition. Recrystallization from aqueous isopropyl alcohol gives material melting at 207208.5 C. (fast heating); 224- 226 C. (slow heating), both with decomposition.

Analysis.Calcd. for C H ClN OS (percent): C, 42.66; H, 3.58. Found (percent): C, 43.14;,H, 3.64.

The above reaction when carried out in the presence of pyridine as a solvent gives material identical with that obtained in Example 68.

EXAMPLE 69 1-{3-amino-5- [2- (2-pyridyl) hydrazino -6-chloropyrazinoyl}thiosemicarbazide 3-amino-5-[2 (2 pyridyl)hydrazino]-6-chloropyrazinoic acid hydrazide (3.4 g.; 0.0115 mole), from Preparation B-3, and potassium thiocyanate (2.23 g.; 0.023 mole) are mixed with N hydrochloric acid (75 ml.) and heated to reflux three hours. The resulting-clear yellow solution is cooled and allowed to stand overnight. The solid that separates is collected and dried to give 1.70 g. (43%) of 1-{3-amino-5 [2 (2 pyridyl)hydrazino]-6- chloropyrazinoyl}thiosemicarbazide, M.P. 226-229" C. (dec.). Recrystallization from dimethylformamide by the addition of acetonitrile gives material melting at 228- 23l C. (dec.).

Analysis.Caled. for C H CIN OS (percent): C, 37.34; H, 3.42; N, 35.65. Found (percent): C, 37.13; H, 3.35; N, 35.40.

EXAMPLE 70 l- (3 ,5 -diamino-6-ch1oropyrazinoyl -4- methylthiosemi car bazide A mixture of 3,5-diamino-6-chloropyrazinoic acid bydrazide (6.06 g.; 0.03 mole), from Preparation B-4, and methyl isothiocyanate (3.67 g.; 0.05 mole) in glacial acetic acid ml.) is heated on the steam bath for two methylthiosemicarbazide, M.P. 270-273 C. (dec.). Recrystallization from hot dimethylformamide gives material melting at 271-273 C. (dec.).

Analysis.Calc. for C H ClN OS (percent): C, 30.49; H, 3.66; N, 35.56. Found (percent): C, 30.70; H, 3.91; N, 35.53.

The above reaction when carried out employing pyridine as the solvent gives the same product.

EXAMPLE 71 1-[3-amino-5-(2,2-pentamethylenehydrazine) -6- chloropyrazinoyl] thiosemicarbazide A solution of 3-amino-5-(2,2-pentamethylenehydrazino)-6-chloropyrazinoic acid hydrazide (5.71 g.; 0.02 mole) from Preparation B2, and potassium thiocyanate (3.88 g.; 0.04 mole) in N hydrochloric acid (40 ml.) is refluxed for two hours. The clear solution then is diluted with water (100 ml.) and neutralized by the addition of dilute ammonium hydroxide. The solid that separates is collected and dried to give 5.89 g. (85%) of 1-[3-amino- 5 (2,2 pentamethylenehydrazino)-6-chloropyrazinoyl] thiosemicarbazide, M.P. 230-233" C. (dec.). Recrystallization from nit-romethane with a little added dimethylformamide gives material melting at 239.5-242.5 C. (dec.).

Analysis.Calc. for C H CIN OS (percent): C, 38.31; H, 4.97; N, 32.50. Found (percent): C, 38.67; H, 5.12; N, 32.55.

EXAMPLE 72 l-{3-amino-5- [2-(2-pyridyl)hydrazino] -6-chloro pyrazinoyl}-4-allyl-3 -thiosemicarbazide 3-amino-5-[2-(2pyridyl)hydrazino] 6-ch1oropyrazinoic acid hydrazide (6.49 g.; 0.022 mole), from Preparation B-3, and allyl isothiocyanate (3.92 g., 0.044 mole) are mixed with glacial acetic acid ml.), and heated on a steam bath with stirring for two hours. The reaction mixture is diluted with water (500 ml.), and neutralized with dilute aqueous ammonium hydroxide ml.). The yellow solid that separates is collected by filtration and dried, yielding 7.9 g. (91% of 1-{3-amino-5-[2-(2-pyridyl)hydrazino] 6 chloropyrazinoyl}-4-allyl-3-thiosemi- 19 carbazide, M.P. 2l8-222 C. Recystallization from dimethylformamide gives material melting at 226-227 C. (dec.).

Analysis.Calc. for C H CIN OS (percent): C. 42.69; H, 4.10; N, 32.01. Found (percent): C, 42.55; H, 4.07; N, 31.94.

Additional 1 (3-amino-5-X-6-Y-pyrazinoyl)thiosemicarbazides prepared by substantially the same procedure described in Example 63 are identified in Table IV. The products are prepared by reacting the pyrazinoic acid hydrazide II with the thiocyanate or isothiocyanate III-b to give the desired product I-b wherein in each of the reactant and end product X, Y and R have the significance given in the following table.

TABLE IV.Continued Hydrazide Ex. from No. Prepn. X Y R 126 13-52 Cl CHzCII=CHz N(CH2)2NH 127 B-53 Cl CHzCH=CH2 Hydrazide known unless otherwise noted.

The novel compounds of this invention can be formulated in the usual oral or parenteral dosage forms for use in therapy in the treatment of conditions resulting from an abnormal electrolyte excretion pattern of an animal organism. It will be appreciated that the dosage of each individual compound will vary over a wide range depending upon the relative potency of the selected compound and also depending upon the age and weight of the particular patient to be treated and upon the particular ailment to be treated. For these reasons, tablets, pills, capsules and the like containing, for example, from to 500 mgs. or more or less active ingredients can be made available to the physician for the symptomatic adjustment of the dosage to the individual patient. As each of the compounds of this invention can be incorporated in a dosage form similar to those described in the following examples, or other usual dosage forms suitable for oral or parenteral administration, which can be prepared by well-known methods, the following examples are included herein solely to illustrate the preparation of representative dosage forms.

EXAMPLE 128 Dry-filled capsule containing 500 mgs. of l-(3-amino-6- chloropyrazinoyl -4-phenylsemicarbazide Mgs/capsule Active ingredient 500 Magnesium stearate 5 Mixed powders 505 Mix the active ingredient and magnesium stearate and reduce to a No. 60 mesh powder. Encapsulate, filling 505 mgs. in each No. 0 capsule.

EXAMPLE 129 Dry-filled capsule containing 50 mgs. of 1-(3,5-diamino- 6-chloropyrazinoyl) -4-allylthiosemicarbazide Mgs/capsule Active ingredient 50 Lactose 273 Magnesium stearate 2 Mixed powders 325 Mix the active ingredient, lactose and magnesium stearate and reduce to a No. 60 mesh powder. Encapsulate, filling 325 mgs. in each No. 0 capsule.

It is also contemplated to combine compounds of this invention in unit dosage form with other known diuretic agents, such as hydrochlorothiazide, 4'-methyl-6-chlorospiro- [2H-1,2,4-benzothiadiazine-3 (4H) -1'-cyc1ohexane] 7-sulfonamide-l,l-dioxide, trichloromethiazide, cyclopenthiazide, acetazolamide, dichlorophenamide, chlorthalidone, chloromerodrin, chlorazanil, spironolactone, and the like or to combine the compounds of this invention with hypotensive agents or steroids or other desired therapeutic agents in suitable dosage form.

While the above examples describe the preparation of certain compounds which are illustrative of the novel compounds of this invention, and certain specific dosage N X NI-I2 7 Y -c ONHNII-C-NH in characterized in that a 3-aminopyrazinoic acid hydrazide of structure II is caused to react with a compound of structure III wherein in each of the foregoing structures X is selected from hydrogen and an amino group having the structure N R R wherein R is selected from (1) hydrogen,

(2) lower alkyl and (3) lower alkenyl;

R is selected from (1) hydrogen,

(2) lower alkenyl,

(3) lower alkynyl,

(4) C cycloalkyl,

(5) phenyl and substituted phenyl, wherein the substituent(s) are selected from halogen, lower alkyl and lower alkoxy,

(6) lower alkoxy,

(7) pyridylamino and pentamethyleneamino,

(8) lower alkyl and substituted lower alkyl wherein the substituent(s) are selected from (a) lower alkoxy,

(b) C cycloalkyl,

(c) furyl,

( py y (e) phenyl and substituted phenyl wherein the substituent(s) are selected from halogen, lower alkyl and lower alkoxy,

(f) NR R wherein R is selected from (i) lower alkyl and (ii) lower alkylcarbonyl, R is lower alkyl and R and R taken together with the nitrogen to which they are attached form a 5-6 membered ring selected from piperidino, pyrrolidinyl, morpholino, piperazinyl, N-lower alkyl piperazinyl, and R and R taken together with the nitrogen to which the structure N X -NH2 ii Y CONHNHCNHR1 wherein X, Y and R have the meaning assigned in claim 1.

3. A process as claimed in claim 1 wherein reactant III has the structure S=C, NR to provide a product having the structure wherein in each of the foregoing compounds X, Y and R have the meaning assigned in claim 1.

4. A process as claimed in claim 1 wherein the reaction is carried out in the presence of a solvent and with heating.

5. A process for the preparation of 1-(3-amino-6-chloropyrazinoyl)thiosemicarbozide comprising heating a solution containing 3-amino-6-chloropyrazinoic acid hydrazide and potassium thiocyanate in an acid medium.

6. A process for the preparation of 1-{3-amino-5-[2-(2- pyridyl)hydrazino] 6 chloropyrazinoyl}thiosemicarbazide which comprises heating a solution containing 3- amino-S-[Z-(Z pyridyl)hydrazino] 6 chloropyrazinoic acid hydrazide and potassium thiocyanate in an acid medium.

7. A process for the preparation of 1-(3,5-diamino-6- chloropyrazinoyl) 4 allylthiosemicarbazide which comprises heating a reaction mixture containing 3,5-diamino- 6-chloropyrazinoic acid hydrazide and allyl isothiocyanate.

8. A compound having the structure wherein X is selected from hydrogen and an amino having the structure -NR R wherein 26 R is selected from 1) hydrogen,

(2) lower alkyl and (3) lower alkenyl;

R is selected from (1) hydrogen,

(2) lower alkenyl,

(3) lower alkynyl,

(4) C cycloalkyl,

(5) phenyl and substituted phenyl, wherein the substituents(s) are selected from halogen, lower alkyl and lower alkoxy,

(6) lower alkoxy,

(7) pyridylamino and pentamethyleneamino,

(8) lower alkyl and substituted lower alkyl wherein the substitlent(s) are selected from (a) lower alkoxy,

(b) C cycloalkyl,

(c) furyl,

( py y (e) phenyl and substituted phenyl wherein the substituent(s) are selected from halogen, lower alkyl and lower alkoxy,

(f) NR R wherein R is selected from (i) lower alkyl and (ii) lower alkylcarbonyl, R is lower alkyl and R and R taken together with the nitrogen to which they are attached form a 5-6 membered ring selected from piperidino, pyrrolidinyl, morpholino, piperazinyl, N-lower alkyl piperazinyl, and R and R taken together with the nitrogen to which they are attached form a 5- to 6-membered ring selected from piperidino, pyrrolidinyl, morpholino, piperazinyl and N-lower alkyl piperazinyl; Y is selected from hydrogen, lower alkyl, halogen and phenyl; Z is selected from oxygen and sulfur; and R is selected from hydrogen, lower alkyl, lower alkenyl phenyl, halophenyl and phenyl-lower alkyl. 9. A product as claimed in claim 8 wherein Z is oxygen and X, Y, R each have the meaning assigned in claim 8. 10. A compound a claimed in claim 8 wherein X is hydrogen, Y is chloro, Z is oxygen and R is phenyl.

11. A compound as claimed in claim 8 wherein X is hydrogen, Y is chlorine, Z is sulfur, and R is hydrogen. 12. A compound as claimed in claim 8 wherein X is 2-pyridylhydrazino, Y is chloro, Z is sulfur and R is hydrogen.

13. A compound as claimed in claim 8 wherein X is amino, Y is chloro, Z is sulfur and R is allyl.

References Cited UNITED STATES PATENTS 3,444,165 5/1969 Pollak et al. 260250 NICHOLAS .S. RIZZO, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent m 3,555 ,024 Dated January 12, 1971 Kenneth J I Edward J. Cragoe, Jr., John B. Bicking & Shepard It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

{- In column 1, line 55 change "ed" to read or-. In

Table I, correct the first structure in Equation A to read as follows: N

Cl I NH2 Cl COOCH3 in Preparation A 6 change the structure in the "R column tc read as follows:

cri- N 2 in Preparation A-8, in the "Calculated N" column, change "42. 34" to read 24. 3.4---; in Preparation A-9 change the structure in the "R column to read as follows:

COCH 3- 2 2- in Preparation A-ll, change the structure in the "R column t read (Cl- H NCH CH in Preparation A-l7, in the "Found N" colLunn, change "5. 17" to read --2l.l7-; in Prepar tion A-l9 correct the structure in the "R column to read as follows C H CH2CH NCH CH in Preparation A-2O correct the structure in the "R column to read -CH CH OCH CH and in Preparation A-2l, in the "Found N column, change "16.55" to read l6.52,. In column 6 line 67, correct the empirical formula to read ,--C 0H 5ClN7O-; line 68 change- "N, 34.22" to read N, 34. 32 in line 71, change "hydrazinol" to read -hydrazino-,---; and in line 72, change "hydrazinol" to read hydrazino. In Table II,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,555 ,024 Dated January 12, 1971 Kenneth L. Inventor) Edward J. Cragoe, Jr., John B. Bicking & Shepard PAGE 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

in Preparation B-l3, change the formula to read --C H ClN O in Preparation 13-43 change the formula in the "X" column to read -CH-CCH NH in Preparation B-46, in the "Y" column, change "C" to read -Cl-; in Preparatior B-47, in the "Y" column, change "C" to read ---Cl-. In column 11, line 21, change the empirical formula to read C H ClN O In Table III, Example No. 52,r correct the structure in the "X" column to read CHECCH NH- column 16 line 52 correct the empirical formula to read --C H ClN- OS-. In column 18 line 30 immediately followix the word "two" add the following:

hours. The reaction mixture is diluted with water (250 ml.) and the resulting solid is collected and dried to give 6 .53 g. (79%) of l-(3,5-diamino-6- chloropyrazinoyl) 4 and in line 42, change "pentamethylenehydrazine" to read -pentamethylenehydrazino-. In Table IV, Example No. 78, correct the structure in the "X" column to read -CH =CHCH NH- and in Example No. 97 in the structure in the "X" column change "CH3N" to read --CH N.

Signed and sealed this 31st day of August 1971.

(SEAL) Attest:

EDWARD Fmmmm RQBIER'I nio'rl'scuAL Attesting Officer Attlng Commissioner of buumt 

